The invention relates to novel substituted diaminocarboxylic acids, processes for their preparation and use thereof as pharmaceuticals for the treatment of connective tissue disorders.
Patent applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonamidohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). Patent application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metalloproteinase inhibitors.
The arylsulfonyl group has furthermore proven useful as an effective protective group of the amino function of xcex1-aminocarboxylic acids (R. Roemmele, H. Rapoport, J. Org. Chem. 53 (1988) 2367-2371).
In the attempt to find active compounds for the treatment of connective tissue disorders, it has now been found that the diaminocarboxylic acids according to the invention are strong inhibitors of matrix metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3) and neutrophil collagenase (MMP-8), since both enzymes are substantially involved, as important constituents of the cartilaginous tissue, in particular in the degradation of the proteoglycans (A. J. Fosang et al., J. Clin. Invest. 98 (1996) 2292-2299).
The invention therefore relates to compounds of formula (I) 
or a stereoisomeric form of the compound of formula (I), or a physiologically tolerable salt of the compound or stereoisomeric form of the compound of formula (I), where
R1 is
1. phenyl,
2. phenyl, which is mono- or disubstituted by
2.1. (C1-C7)-alkyl, which is linear, cyclic, or branched,
2.2. xe2x80x94OH,
2.3. (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94,
2.4. (C1-C6)-alkyl-Oxe2x80x94,
2.5. (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94,
2.6. halogen,
2.7. xe2x80x94CF3,
2.8. xe2x80x94CN,
2.9. xe2x80x94NO2,
2.10. HOxe2x80x94C(O)xe2x80x94,
2.11. (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94,
2.12. methylenedioxo,
2.13. R4xe2x80x94(R5)Nxe2x80x94C(O)xe2x80x94, or
2.14. R4xe2x80x94(R5)Nxe2x80x94, or
3. a heteroaromatic ring structure as defined under 3.1. to 3.16., which is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. indole,
3.12. benzothiophene,
3.13. benzimidazole,
3.14. benzoxazole,
3.15. benzothiazole, or
3.16. benzotriazole;
R2, R4 and R5 are identical or different and each independently are
1. a hydrogen atom,
2. (C1-C6)-alkyl-,
3. HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-,
4. phenyl-(CH2)oxe2x80x94, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and o is the integer zero, 1, or 2,
5. picolyl, or
6. R4 and R5 together with the ring amino group form a 4- to 7-membered ring, in which one of the carbonyl atoms is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94;
R3 and G are identical or different and each independently are
1. a hydrogen atom,
2. (C1-C6)-alkyl-, in which alkyl is linear, branched, or cyclic,
3. (C2-C6)-alkenyl-,
4. phenyl-(CH2)mxe2x80x94, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
5. heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
6. R6xe2x80x94C(O)xe2x80x94, in which
R6 is
6.1. (C1-C6)-alkyl-, in which alkyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., or by (C3-C6)-cycloalkyl,
6.2. (C3-C6)-cycloalkyl, in which cycloalkyl is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14.,
6.3. (C2-C6)-alkenyl-, in which alkenyl is unsubstituted, or mono-, di-, or trisubstituted by
6.3.1. phenyl, in which phenyl is unsubstituted, or mono-, di-, or trisubstituted by the radicals as defined under 2.1. to 2.14.,
6.3.2. heteroaryl-, in which heteroaryl is as defined under 3.1. to 3.16., and is unsubstituted, or mono-, di- or trisubstituted by the radicals as defined under 2.1. to 2.14., or
6.3.3. the radicals as defined under 2. 1. to 2.14.,
6.4. phenyl-(CH2)mxe2x80x94, in which phenyl is unsubstituted, or mono-, di- or trisubstituted by the radicals as defined under 2.1. to 2.14., xe2x80x94Oxe2x80x94CF3, xe2x80x94SO2xe2x80x94NH2, xe2x80x94NHxe2x80x94C(O)xe2x80x94CF3, or by benzyl, a hydrogen atom of the xe2x80x94(CH2)xe2x80x94radical is optionally substituted by the radical xe2x80x94COOH, and m is the integer zero, 1, 2, or 3,
6.5. naphthyl,
6.6. adamantyl, or
6.7. heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3,
7. R6xe2x80x94Oxe2x80x94C(O)xe2x80x94, in which R6 is as defined above,
8. R6xe2x80x94CH(NH2)xe2x80x94C(O)xe2x80x94, in which R6 is as defined above,
9. R8xe2x80x94N(R7)xe2x80x94C(O)xe2x80x94, in which
R8 is
9.1. a hydrogen atom
9.2. (C1-C6)-alkyl-,
9.3. phenyl-(CH2)m, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3, or
9.4. heteroaryl-(CH2)m, in which heteroaryl is as defined under 3.1. to 3.16., is unsubstituted, or is substituted by the radicals as defined under 2.1. to 2.14., and m is the integer zero, 1, 2, or 3, and in which
R7 is a hydrogen atom, or (C1-C6)-alkyl, or in which
R7 and R8 are bonded to a nitrogen atom to form a 4- to 7-membered ring and the ring is unsubstituted, or a carbon atom in the ring is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94,
10. R6xe2x80x94SO2xe2x80x94, in which R6 is as defined above,
11. R6xe2x80x94SO2xe2x80x94N(R7)xe2x80x94C(O)xe2x80x94, in which R6 and R7 are as defined above,
12. R6xe2x80x94NHxe2x80x94C(xe2x95x90NR7)xe2x80x94, in which R6 and R7 are as defined above, or
12.1. (C1-C6)-alkyl-C(O)xe2x80x94,
12.2. xe2x80x94NO2, or
12.3. xe2x80x94SO2xe2x80x94(CH2)q-phenyl, in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and q is the integer zero, 1, 2, or 3, 
xe2x80x83in which m is the integer zero, 1, 2, or 3, and W is a nitrogen, oxygen, or sulfur atom; or
R3 and G are bonded to a nitrogen atom to form a ring of subformulae (IIa) to (IIp), 
xe2x80x83where r is the integer 1 or 2, R10 is a radical as defined under 2.1. to 2.14., and R7 and m are as defined above, and in subformula (IIg) a carbon atom in the ring is optionally replaced by oxygen, sulfur, SO2, or a nitrogen atom which is unsubstituted or substituted by R2;
A is
a) a covalent bond,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94CHxe2x95x90CHxe2x80x94, or
d) xe2x80x94Cxe2x89xa1Cxe2x80x94;
B is
a) xe2x80x94(CH2)mxe2x80x94, in which m is as defined above,
b) xe2x80x94Oxe2x80x94(CH2)q, in which q is the integer 1, 2, 3, 4, or 5, or
c) xe2x80x94CHxe2x95x90CHxe2x80x94;
D is xe2x80x94(CH2)mxe2x80x94 in which m is the integer 1, 2, 3, 4, 5, or 6, and one of the chain carbon atoms is optionally replaced by an optionally substituted xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 atom; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94, an oxygen atom, or a sulfur atom.
A currently preferred compound of formula (I) is where
R1 is
1. phenyl, or
2. phenyl, which is monosubstituted by
1. halogen, in particular chlorine or fluorine, or
2. R4xe2x80x94(R5)Nxe2x80x94, where R4 and R5 are identical or different and each independently are
2.1. (C1-C3)-alkyl, or
2.2. R4 and R5 together with the ring amino group form a 5- or 6-membered ring, where one of the carbon atoms is optionally replaced by xe2x80x94Oxe2x80x94or xe2x80x94NHxe2x80x94;
R2 is a hydrogen atom;
G and R3 are different, and where
G is a hydrogen atom, or (C1-C4)-alkyl, and
R3 is
1. phenyl-(CH2)m, in which phenyl is unsubstituted, mono- or disubstituted by the radicals as defined under 2.1. to 2.14., and m is the integer 1,
2. heteroaryl-(CH2)n, in which heteroaryl is as defined under 3.10. and is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and n is zero,
3. is R6xe2x80x94C(O)xe2x80x94, in which
R6 is
3.1. (C1-C6)-alkyl-, in which alkyl is linear, branched, or cyclic,
3.2. phenyl-(CH2)rxe2x80x94 in which phenyl is unsubstituted, or mono- or disubstituted by the radicals as defined under 2.1. to 2.14., a hydrogen atom of the xe2x80x94(CH2)xe2x80x94 radical is optionally replaced by the radical xe2x80x94COOH, and r is zero, 1, 2, or 3, or
3.3. heteroaryl-(CH2)oxe2x80x94, in which heteroaryl is as defined under 3.1. to 3. 15., and is unsubstituted, or substituted by the radicals as defined under 2.1. to 2.14., and o is zero, 1, 2, or3, or
4. is R8xe2x80x94N(R7)xe2x80x94C(O)xe2x80x94, in which
R8 and R7 are bonded to a nitrogen atom to form a 5- or 6-membered ring, in which the ring is unsubstituted, or a ring carbon atom is replaced by an oxygen atom, or
R3 and G are bonded to a nitrogen atom to form a ring of subformula (IIg), in which r is 1;
A is a covalent bond;
B is xe2x80x94(CH2)pxe2x80x94, in which p is zero;
D is xe2x80x94(CH2)qxe2x80x94, in which q is the integer 2, 3, or 4; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94.
The expression xe2x80x9cR4 and R5 together with the ring amino group form a 4- to 7-membered ring, in which one of the carbon atoms is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94xe2x80x9d is understood as meaning radicals which are derived, for example, from pyrrolidine, piperazine, morpholine, piperidine, or thiomorpholine. The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine, or iodine. The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkenylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chains are straight-chain or branched. Cyclic alkyl radicals are, for example, 3- to 6-membered monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, which may or may not have substituent groups attached to the ring. The alkenyl radicals can furthermore also contain one or more double bonds.
The starting substances of the chemical reactions are known or one of ordinary skill in the art can easily derive and prepare such starting substances by methods known from the literature.
The invention furthermore relates to a process for the preparation of a compound of formula (I), or a stereoisomeric form of a compound of formula (I), or a physiologically tolerable salt of a compound or stereoisomeric form of a compound of formula (I), which comprises
a) reacting a diaminocarboxylic acid of formula (III), 
xe2x80x83in which R2, R3, D, and G are as defined in formula (I), with a sulfonic acid derivative of formula (IV) 
xe2x80x83in which R1, A, and B are as defined in formula (I), and Y is a halogen atom, imidazolyl, or xe2x80x94OR9, in which R9 is a hydrogen atom, (C1-C6)-alkyl, phenyl, succinimidyl, benzotriazolyl, or benzyl, optionally substituted, in the presence of a base or if appropriate of a dehydrating agent, to give a compound of formula (I); or
b) reacting a diaminocarboxylic acid ester of formula (V), 
xe2x80x83in which R2, R3, D, G, and R9 are defined as above, with a sulfonic acid derivative of formula (IV) under the above defined conditions to give a compound of formula (VI) 
xe2x80x83and converting the compound of formula (VI) into a compound of formula (I) with removal of the radical R9, preferably in the presence of a base or acid;
c) reacting the protected diaminocarboxylic acids of formula (VII); 
xe2x80x83in which R2 and D are as defined above, and E is a protective group of the amino function, with a sulfonic acid derivative of formula (IV), to give a compound of formula (VIII) 
xe2x80x83and then converting the compound of formula (VIII), by removal of the protective group E with the aid of suitable cleavage agents, into a compound of formula (I) 
xe2x80x83in which R1, R2, A, B, D, and X are as defined above, and R3 and G are both hydrogen atoms, and reacting this compound of the formula (I) if appropriate with the aid of R3xe2x80x94Y, in which R3 and Y have the meanings defined above, in the presence of a base to give a compound of formula (I), 
xe2x80x83in which R1, R2, R3, A, B, and X are as defined above, and G is a hydrogen atom; or
d) as starting compounds, converting protected diamino acid esters of formula (IX), 
xe2x80x83in which R2, R9, D, and E are as defined above, in the same manner as described in process variant c), into the esters of formula (X), 
xe2x80x83which are optionally converted into the corresponding compounds of formula (I) according to process variant b); or
e) coupling a diaminocarboxylic acid of formula (XI), 
xe2x80x83in which D is defined as in formula (I), and E and F are N-amino protective groups which are different from one another, by its carboxyl group xe2x80x94C(xe2x95x90O)Oxe2x80x94 via an intermediate chain L to a polymeric resin depicted as PS, resulting in a compound of formula (XII) 
xe2x80x83which, after selective removal of the protective group F, is reacted with a sulfonic acid derivative of formula (IV) 
xe2x80x83where R1, A, B, and Y are as defined above, in the presence of a base or, if appropriate, of a dehydrating agent, to give a compound of formula (XIII) 
xe2x80x83and reacting the compound of formula (XIII), after removal of the protective group E, with a carboxylic acid derivative of formula (XIV)
R6xe2x80x94C(O)xe2x80x94Yxe2x80x83xe2x80x83(XIV)
xe2x80x83in which R6 and Y are as defined above, in the presence of a base or of a dehydrating agent, to give a compound of formula (XV) 
xe2x80x83and converting this, after removal from the support material, into a compound of formula (I), 
xe2x80x83in which R1, R6, A, B, D, and X are defined as above.
Starting compounds of formula (III) employed in which R2, R3, and G are a hydrogen atom preferably included 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine and homolysine. If R3 and G, together with the amino function, are a guanidyl group, arginine is preferably used.
If, as in process variants c), d) and e), the amino functions of the starting compounds of formulae (VII), (IX) and (XI) are provided with a protective group E or F, this selective amino group derivatization is carried out according to methods such as are described in Houben-Weyl Methoden der Org. Chemie [Methods of Organic Chemistry], Volume 15/1 (1993).
Suitable protective groups E and F for this purpose are preferably the N-protective groups customarily used in peptide chemistry, for example protective groups of the urethane type, such as benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenyl-methoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc), or of an acid amide type, in particular formyl, acetyl, or trifluoroacetyl, or of an alkyl type such as benzyl. The (trimethylsilyl)ethoxycarbonyl (Teoc) group has proven particularly suitable for this purpose (P. Kocixc3xa9nski,-Protecting Grups, Thieme Verlag, 1994). Many of the selectively derivatized compounds are also commercially available, so the preparation of the compounds of formula (I) according to the invention, as described in process variant c), comprises carrying out, after the introduction of the sulfonic acid ester into the xcex1-amino group, the removal of the side-chain protective group E, which can optionally be followed by a multi-stage derivatization of the free amino group in the side chain. During this procedure, the carboxyl group can be present in free form or in the form of an ester with the radical xe2x80x94OR9. In the case in which the radical xe2x80x94OR9 is a straight-chain (C1-C3)-alkyl radical, this ester of formula (I) can also be employed in therapy in this form (as a prodrug). When R9 is a tert-butyl radical, the ester cleavage is preferably carried out according to known methods using HCl in diethyl ether or trifluoroacetic acid in the last synthesis stage.
Starting materials for the preparation of the sulfonic acid derivatives of formula (IV) are preferably sulfonic acids or their salts of the formulae (XVIa)-(XVIg), for example: 
where R10 is a radical as defined under 2.1. to 2.14.
For the preparation of the arylsulfonic acids of formulae (XVIa) and (XVIb), use is preferably made of the sulfonation processes using concentrated sulfuric acid described in Houben-Weyl Methoden der Organischen Chemie [Methods of Organic Chemistry], Volume 9 (1993), pp. 450-546, if appropriate in the presence of a catalyst, sulfur trioxide and its addition compounds or halosulfonic acids, such as chlorosulfonic acid. Particularly in the case of the diphenyl ether of formula (XVIb), the use of concentrated sulfuric acid and acetic anhydride as solvents (C. M. Suter, J. Am. Chem. Soc. 53 (1931) 1114), or the reaction with excess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinbourne; Phosphorus, Sulfur and Silicon 72 (1992) 157) has proven suitable. Sulfonic acids according to the formulae (XVIc), (XVId), or (XVIe) can be prepared in a known manner in which the corresponding arylalkyl halide is reacted with sulfites such as sodium sulfite or ammonium sulfite in aqueous or aqueous/alcholic solution. It is possible to accelerate the reaction in the presence of tetraorganoammonium salts such as tetrabutylammonium chloride.
The sulfonic acid derivatives according to formula (IV) are in particular the sulfonyl chlorides. For their preparation, the corresponding sulfonic acids, also in the form of their salts such as sodium, ammonium or pyridinium salts, are reacted in a known manner with phosphorus pentachloride or thionyl chloride without or in the presence of a solvent such as phosphorus oxytrichloride or of an inert solvent such as methylene chloride, cyclohexane or chloroform, in general at reaction temperatures from 20xc2x0 C. up to the boiling point of the reaction medium used.
The reaction of the sulfonic acid derivatives of formula (IV) with the amino acids of formulae (III), (V), (VII) or (IX) according to process variant a), b), c) or d) proceeds advantageously in the manner of a Schotten-Baumann reaction. Suitable bases for this purpose are particularly alkali metal hydroxides such as sodium hydroxide, but also alkali metal acetates, hydrogencarbonates, carbonates and amines. The reaction takes place in water or in a water-miscible or immiscible solvent such as tetrahydrofuran (THF), acetone, dioxane or acetonitrile, the reaction temperature in general being kept at from xe2x88x9210xc2x0 C. to 50xc2x0 C. In the case in which the reaction is carried out in anhydrous medium, tetrahydrofuran or methylene chloride, acetonitrile or dioxane in the presence of a base, such as triethylamine, N-methylmorpholine, N-ethyl- or diisopropyl ethyl amine, is especially used, possibly in the presence of N,N-dimethylaminopyridine as the catalyst.
In another variant, the aminocarboxylic acids of the formulae (III), (V), (VII) or (IX) can first be converted into their silylated form with the aid of a silylating agent such as bis-trimethylsilyltrifluoroacetamide (BSTFA) and they can then be reacted with sulfonic acid derivatives to give compounds of formula (I).
The polymeric support designated by PS in formula (XII) is a crosslinked polystyrene resin having a linker designated L as an intermediate chain, known as a Wang resin (S. W. Wang, J. Am. Chem. Soc. (1973), 1328, p-benzyloxybenzyl alcohol polystyrene resin). Alternatively, other polymeric supports such as glass, cotton or cellulose having various intermediate chains L can be employed.
The intermediate chain designated by L is covalently bonded to the polymeric support and allows a reversible, ester-like bonding with the diamino acid of formula (XI), which during the further reaction remains stably bonded to the diaminocarboxylic acid, but under strong acidic reaction conditions (e.g., pure trifluoroacetic acid) releases the group located on the linker again.
The release of the desired compound of the formula (I) from the linker can be carried out in various places in the reaction sequence.
1) In the case of a compound of the formula (I) in which R3 and G are hydrogen, the xcex1-sulfonylamino-xcfx89-carboxylic acid derivative, after removal of the protective group E, is liberated by treatment of the resin with trifluoroacetic acid.
2) If a compound of formula (I) in which R3 is hydrogen and G is R6xe2x80x94C(O)xe2x80x94 is to be obtained, the release of the compound from the resin is carried out after simple acylation with R6xe2x80x94C(O)xe2x80x94Y, as in 1).
3) For the case of a compound of formula (I) in which R3 and G are R6xe2x80x94C(O)xe2x80x94, the removal is only carried out after thorough diacylation with the aid of an acylating catalyst, e.g., dimethylaminopyridine, as in 1).
4) This procedure furthermore allows the radicals 2. to 13. defined in formula (I) for R3 and G to be coupled at this position in the reaction sequence to the xcex1-sulfonylamido-xcfx89-aminocarboxylic acid bonded to the solid support using suitable reagents, e.g., alkyl halides, alkenyl halides, chloroformates, isocyanates, sulfonic acid derivatives, or cyclic anhydrides. After removal of the resulting compounds from the solid support, the corresponding substituted amines, urethanes, ureas, sulfonamides or amides, for example, are thus also obtained.
A. General procedure for the coupling of protected diaminocarboxylic acids of formula (XI) to the solid support according to procedure e): 2 g of Wang resin (Nova-Biochem; loading 0.5 mmol/g) are allowed to swell in 20 ml of dry dichlormethane for 30 min (50 ml PET syringe with a Teflon filter on the syringe bottom). After filtering the solvent, the syringe is filled with a solution of 3.5 mmol of the appropriate xcfx89-Teoc-xcex1-Fmoc diaminocarboxylic acid (prepared according to D. H. Rich et al., Synthesis 198, 346), 3.5 mmol of diisopropylcarbodiimide and 0.5 mmol of N,N-dimethylaminopyridine in approximately 10 ml of dry dichloromethane and shaken at room temperature (RT) for 16 hours (h).
After filtering off the reaction mixture, the resin is washed several times with dichloromethane and dried and weighed to determine the yield.
B. Removal of the xcex1-Fmoc protective group: The resin prepared as in A. is allowed to swell in the syringe in approximately 20 ml of dry dimethylformamide (DMF) and then, after filtering off the solvent, treated with 25% strength piperidine/DMF solution and shaken at RT for 45 minutes (min). The resulting mixture is filtered and the resin remaining in the syringe is washed several times with dry DMF. (The filtrate and all wash solutions can be stored to determine the Fmoc removal; for implementation see: Solid Phase Peptide Synthesisxe2x80x94A Practical Approach, E. Atherton and R. C. Sheppard, IRL Press at Oxford University Press 1989).
C. Sulfonation of the free xcex1-amino group: The contents of the syringe are then uniformly distributed into four smaller syringes provided with an inserted filter plate and treated with solutions of various sulfonic acid derivatives of formula (IV) (in each case 1 mmol) and diisopropylethylamine (in each case 1 mmol) in 3 ml of dry DMF and shaken at RT for 24 h. The reagent solution is then washed out and the resin is washed several times with DMF.
D. Removal of the Teoc protective group: The resin prepared as in step C. is treated with a molar N-tetrabutylammonium fluoride solution in DMF (in each case approximately 3 ml) and shaken at RT for 2 h. The reagent solutions are filtered and the remaining resin is washed several times with DMF. The syringe contents of each of the 4 individual syringes are then distributed, for example, into each of a further 3 prepared syringes. (In each case 1xc3x970.05 mmol and 2xc3x970.1 mmol).
E.1: Removal from the solid support: In each case approximately ⅕ of the contents of a syringe is washed with dichloromethane (approximately 10 ml) to remove the substance from the solid support, dried and shaken at RT for 1 h with approximately 1 ml of a solution of 95% trifluoroacetic acid, 2% H2O, and 3% triisopropylsilane.
The filtered solution from the syringe is evaporated, and precipitated with diethyl ether. The solid residue is filtered for further purification and dried.
E.2: Acylation with carboxylic acid derivatives of the formula R6xe2x80x94C(O)xe2x80x94Y: The other syringes are in each case filled with 1 molar solutions of acetic anhydride (1 equivalent based on liberated amine, or 3 equivalents for bis-acylations) and a corresponding amount of triethylamine in DMF and shaken at RT for 16 hours (completeness of the acylation can be checked, for example, by the Kaiser-Ninhydrin test (for implementation see: Solid Phase Peptide Synthesisxe2x80x94A Practical Approach, E. Atherton and R. C. Sheppard, JRL Press at Oxford University Press 1989).
E.3: Removal of the compounds of formula (XV) from the solid support: The resins prepared in E.2: are washed with dichloromethane as described in E.1:, dried and treated at RT for 1 h with trifluoroacetic acid/H2O/triisopropylsilane 95/2/3. The solutions obtained are worked up as described in E.1:.
Physiologically tolerable salts are prepared from compounds of formula (I) capable of salt formation, including their stereoisomeric forms, in a manner known to those skilled in the art. With basic reagents, such as hydroxides, carbonates, hydrogencarbonates, alcoholates and also ammonia or organic bases (e.g. trimethyl- or triethylamine, ethanolamine or triethanolamine) or, alternatively, basic amino acids (e.g. lysine, ornithine or arginine) the carboxylic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts. If the compounds of formula (I) have basic groups, stable acid addition salts can also be prepared with strong acids. Those suitable for this purpose are both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic, or trifluoroacetic acid.
The invention also relates to pharmaceuticals comprising an efficacious content of at least one compound of formula (I), or an optionally stereoisomeric form of the compound of formula (I), or of a physiologically tolerable salt of the compound or of the stereoisomeric form of the compound of formula (I), together with a pharmaceutically suitable and physiologically tolerable excipient, additive or other active or inactive compounds and auxiliaries.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in the course of which an increased activity of matrix-degrading metalloproteinases is involved. These include degenerative joint disorders such as osteoarthroses, spondyloses, chondrolysis after joint trauma or relatively long immobilization of the joint after meniscus or patella injuries or tears of the ligaments. Furthermore, these also include disorders of the connective tissue such as collagenoses, periodontal disorders, wound healing disorders and chronic disorders of the locomotory apparatus such as inflammatory, immunologically or metabolically related acute and chronic arthritides, arthropathies, myalgias and disorders of the bone metabolism. The compounds of formula (I) are furthermore suitable for the treatment of ulceration, atherosclerosis and stenoses. The compounds of formula (I) are furthermore suitable for the treatment of inflammation, carcinomatous disorders, formation of tumor metastases, cachexia, anorexia and septic shock.
The pharmaceuticals according to the invention are in general administered orally or parenterally. Transmucosal (such as rectal) and transdermal administration are also possible.
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of formula (I) into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, other suitable active compounds, additives or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and also preparations with protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubiliizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut, or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably prepared and administered in dose units, each unit as active constituent containing a specific dose of the compound of formula (I) according to the invention. In solid dose units such as tablets, capsules, coated tablets, or suppositories, this dose can be up to approximately 1000 mg, but the currently preferred dose is approximately 50 to 300 mg, and in injection solutions in ampoule form up to approximately 300 mg, but the currently preferred dose is approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compounds according to formula (I), daily doses of approximately 20 mg to 1000 mg, preferably approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, higher or lower daily doses may be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of several smaller dose units and by multiple administration of subdivided doses at specific intervals. 1H-NMR spectra have been recorded on a 200 MHz apparatus from Varian, as a rule using tetramethylsilane (TMS) as an internal standard and at room temperature (RT). The solvents used are indicated in each case. As a rule, final products are determined by mass-spectroscopic methods (FAB-, ESI-MS). Temperature data are given in degrees Celsius, RT means room temperature (22-26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions unless specified otherwise.